Alkoxyalkyl iodobenzoates



Patented Sept. 30,1952

1- :flDelaware;

messing,imitatio o e ta 2e1tie- 3 Serial No. sm-s53 Y is .Glaimsm (c1. 260-. 476) where Y is an alkylene bridge and R is alkyl, and wherein the total number of carbon atoms in the above formula is from lfltto 18. I prefer the compounds-wherein Yihas 2-3 carbon atoms and R has 1+6 carbon atoms, since these are most readily available from rinex-pensivestarting materialsrrMy compoundsg -are opaque to X-rays and therefore are yaluable -as -contrast media in roentgenological examination of body cavities. They may be administered-directly. into the body cavities to ,be outlined. The-y are-definit and stable chemical compounds in which the halogen is firmly attached to the phenyl radical.

I have found that these substances, are of particular value in the roentgenolog'ical examination of the spinalcord' and subarachnoid space, i. e., in that branch of radiography known as myelography; AIL idealnnyelographic: agent, is i one" which :eaa'lramr rapidlyadmini'stered; and

may be distributed readily and evenly to various difliciiltto administer properly, since their; requires replacement of part of the cerebrospinal fluid with gas, a procedure which may result in dangerous complications. Thorium idioxide sols lack the objectionable qualities of gases but have been found to'--cause uhtowardreactions, as well as introducing the possibility of eventual injury rum res l rad oact ty ifid natedzandbrominated oils such as i-odinated poppyseedssoil'. 1;

iodinated sesame oil, iodinated rapeseed oil and :brommated olive oil, are effective and non-toxic contrast agents, but are largely iunsatisfactory because of their highnviscosity and somewhat irritating properties? "Ihey' m'ustbe injected.

5 contact with the tissues.

' FA'LKOXYALLKY'L IODOBIENZOATESQ" syfln'ey'Archer Albany, N. Y.,-assig:1or toStei-ling Drug Inc; Wilniington, Del.,;::a. corporation of under'zpre'ssur'e and-rafterrexamlnation be with:

drawn :by; aspiration, wfor J otherwisesth-ey remainlargely unabsorbed for a period of years,--,. a-nd;, cicatrix formation mayresult from prolonged Their high viscosity tends-tocause --separationo'f the'oillinto globules,

rendering diagnosis f'di'fllculti' The ilmixtiire'ai of; ethyl iiodophenylundecylates: is i.undoubted1y::-the: best unyelUgraphic. A agent :previ'ously -sprodnce'ad;v .It' i's less viscous than the Iio dinated-iglyceride;

7 oils and, therefore; 1 is more iea'silyintroduced-y withdrawn f'a'n'd absorbed. "Howeveryz'itr-is re:-': ported that L'ati least a .year "is 'irequire'd for i-the Although the possibility" ofzusingfwateresoiubie' radiopaqu'e :m'edia :as v myelographic' :agents: has;

been investigated,- qthes'eseompounds "haveibeeii: found unsatisfactory :for numbermii-greasontiz Diffusion is so rapid thatethercompoundbecomes diluted with spinal fluid, tlfiereby losing its radiopacity unless a large duan'tit'yis, injected, whereupon toxicity-becomes5anrimportantIactonsince watersoluble; substances-Vere :rapidly absorbed-,- into the circulatoryfsystem a i u The" :1ralkbkyalkylz'l monoio dobenzoates; have: many advantages-zover-th'e abdveedescribedumy 11 logr'aphic :age'ntsiiz For: instancez'theyiare muclmn moreweadily; eliminated from (the organism: that aspirations for removal .-is' not i reguin, They -cause little or fnoyirritation ,ofgrnembren 'su w t wh chtheyacomezinr nta -i Exp r menta studies with several :compounds the; scope of this invention have shown that apprec i a b1e, amounts are completely eliminated from the cerebrospinal system of? rabbits or cats within ten to twenty five dayswitn;ens estease bein gonein a few'daysx Sim; a'rexperiments than shown by ztne riew compon'ir toxicities of' 'my. new."rcompoundsforally:and i traperitone'ally arezlowfenoughitopermiirtheicom pounds: tob'e saielylused as: myelographmmgema.

The esters of my invention havestlfe advantagfi of being pure compounds inst-ead of a mixture undeoylatei Yr 1 t a My new :c mpounds can" be synthes zed" complete "absorption an'd. elimination of"aselittl'ei acidis refluxed for sixteen hours. mixtur'e'tis pouredintoice-water, the product is extracted with ether; and the ether layer washed with water; sodium" carbonate solution,

one of the following methods: (1) the iodobenzoic acid and an alkoxyalkanol are combined directly in the presence of, an acid catalyst; (2) said acid in the form of a reactive derivative, such as the acid chloride or anhydride, is caused to react with an alkoxyalkanol; or (3) a metallic salt of saidacid is caused to react with an alkoxyalkyl- 'halide. The following alkoxyalkanols are representative of the alcohols from which my new compounds are derived: 2-methoxy-- ethanol, Z-ethoxyethanol, Z-propoxyethanol, 2-,

butoxyethanol, 3-methoxy-l-propanol, 3-ethoxy-' l-propanol, 3-m-ethoxy-2-propanol, .3-ethoxy-2- propanol, 4-methoxy-l-butanol, S-methoxy-lpentanol, and 2-(beta-ethylbutoxy)-ethan0l.

The corresponding halides, inwhich the hydroxvl groups are replaced by halogen, may be used if method (3) is employed.

The following examples will illustrate my invention more completely, but should not be construed as a limit to the scope'of the invention, this-being determined instead bythe appended claims.

E cidmple l p Z-Methowyethyl p-iodobenzoate.-A mixture of 30.g:.of.p -iodobenzoic acid and 110 cc. of thionylv chloride is'refluxedfor twentyhours on a steam bath.. The excess thionyl chloride is removed at reduced pressure, 55 cc. of 2-methoxyethano1 for one hour. The reaction -mixture is then pourediinto' ice-water, and the product is extracted with- .ether. .The ether extracts are Washed with water, 10% sodium carbonate solution;.and again withwater, and dried over anhydrousrsolium .sulfate.- Afterremoval of volatile solvents, 2-methoxyethyl p-iodobenzoate distilsat'144-146 C- (0.7 mm.) yield about 32 g. Viscosity,;13;8 centistokes. r .Ezdmple 2 v Z-methoxyethyl m-iodobenzoata-A mixtur 0124 ggOf m-iodobenzoic acid, 115 cc. of 2-methoxyethanol and 2 odor-concentrated sulfuric The reaction again with water, and" dried over-anhydrous sodium sulfate. After" removalof 'volatil'e solvents,=2-methoxyethyl m-io'dobenzoate distils at 142 145 1c (o.6 mm.) yield about V iscOs' Example 3 alethoi'yethyl p-iodobenzoata-A mixture of oxyethanol and cc. of dry benzene is refluxed Ol Iifg. steam bath for three hours. The benzene isremoved at; reduced pressure and the reaction mixture poured into ice-waten The'product is extractedwith ether,washed with water, 10%

sodium carbonate solution, again with water and then iis gdried" over. anhydrous sodium sulfate. After removalof volatile solvents, 2- ethoxyethyl p.-:iodobenzoatejdistils at 122-125 C. (0.04 mm.)

yield' about sags; V

.. Ex p e l 1 I gz-etlioxyethyl m-iodobenzoata-A mixture of 24fgmimriodobenzoicflacid, 150cc. of 2-ethoxyadded,--an'd the mixture is heated on a steam bath v where R is an alkyl group of 1 to 6 carbon atoms; 3. 2-methoxyethyl m-iodobenzoate having the:

ethanol and 2 cc. of concentrated sulfuric acid is caused to -react and isi'worked up as in Example 2..;:%T 1'1.e;2ethoxyethyl'm-iodobenzoate thus obtained distils at 14'7-150" C. (0.8 mm.); yield about 21 g. Viscosity 14.0 cs.

Example 5 Z-ethoxyethyl o-z'odobenzoate.A mixture of 57.8 g. of o-iodobenzoyl chloride and 36.7 g. of 2-ethoxyethanolis heated on the steam loath for about one-hour. Air is bubbled' through the mixture to remove hydrogen chloride and the product is distilled giving a fraction boiling at l12-125 C. (0.07 mm.), about 64 g. Two additional distillatiohs of this fraction gives the pure 2-ethoxyethyl o-iodobenzoate, B. P. 108-110 C.

1. A compound having the formula where? is an alkylene bridg'e of from 2 '5':

carbon atoms and at least two carbon atoms separate the carboxyl group from the --OR group. and R is an alkyl' group of from 1 to 6 carbon atoms, said compoundhaving a total orrm 10 to Iii-carbon atoms.

2; A-compound having the' -formula formula- I COOCHbCHzOCH:

cooo'mcmoomom formula -6; 3-ethoxypropyl pjiodobenzo ate, having the formula 4. 2- ethoxyethy1 p-iodobenzoatef v h h im v v f5; z-ethoxyethyl m-iodobenz oate, h y ng.

V CCOCH ClimCEfic 1 6 r 7. 3-methoxypropy1 p-iodobenzoate, having the REFERENCES CITED formula The following references are of record in the I file of this patent:

5 -UNITED STATES PATENTS I C O O CHaCH=OH=O CH; Number Name Date 2,198,583 Gretheret a1. Apr. 23, 1940 8- A p u d having t ula 2,234,374 Grether et a1. Mar. 11, 1941 I 10 FOREIGN PATENTS I Number Country Date COOCHzCHzCHz-O-R I 517,382 Great Britain July 25, 1939 517,425 Great Britain Jan. 30, 1940 where R is an alkyl group of 1 to 6 carbon atom S. OTHER REFERENCES O'Donnell et"a1.: J.,Am. Chem. Soc., vol. 68, D. 1865, (1946). v

SYDNEY ARCHER. 15

.Polomma: Ber. Deut. Chem., vo1. 42, p. 3376,

r (1909). I r 

1. A COMPOUND HAVING THE FORMULA 